In the present analyses, we found that high consumption of whole-grain bread was significantly associated with modestly lower levels of GGT, ALT and hs-CRP, whereas high consumption of red meat was significantly associated with higher levels of GGT and hs-CRP after adjustment for potential confounding factors related to lifestyle and diet. After further adjustment for body mass index and waist circumference, the association between red meat consumption and hs-CRP was no longer statistically significant, suggesting that the degree of adiposity may explain this association and obesity may thus be considered as a potential intermediate factor. The results of the present study also suggest that the relation of red meat consumption with higher hs-CRP levels may be modified by higher whole-grain bread consumption or factors closely related to it.
The observed inverse association between whole-grain bread consumption and plasma CRP levels is in line with a cross-sectional analysis among 902 diabetic women in the Nurses’ Health Study, which suggested that consumption of whole grains and cereal fiber was associated with lower inflammatory markers such as CRP and soluble TNF receptor 2 [14
]. Another study in a multi-ethnic sample of 5,496 men and women suggested an inverse association between whole-grain consumption and CRP levels [15
]. However, in an analysis based on a subset of men from the Health Professionals Follow-Up Study and women from the Nurses’ Health Study II, the significant association between whole-grain intake and serum CRP disappeared after adjustment for lifestyle factors, including alcohol intake, smoking, BMI, physical activity and hypercholesterolemia [16
]. Furthermore, recent trials on the effect of substitution of refined grain products with whole-grain wheat or oat products have been inconclusive [17
]. In recent comprehensive intervention trials among 316 overweight participants [18
] and among 206 participants with normal weight [17
], neither three servings of whole-grain foods per day for 12 weeks nor 120 g/day for 16 weeks significantly affected plasma CRP levels. In both interventions, the authors discussed that diets of high whole-grain consumers in these intervention studies were different from that of high whole-grain consumers in observational studies, and whole-grain consumption may be a marker of an otherwise healthier diet. However, in the present study, the association was observable even after comprehensive adjustment for dietary factors. The null findings in intervention studies suggest that the observation may still be confounded.
Of the biomarkers of dyslipidemia, glucose metabolism and insulin sensitivity consumption of whole-grain foods were related to lower LDL-cholesterol but not to HDL-cholesterol or triglyceride or HbA1c concentrations after adjustment for lifestyle and dietary factors in Framingham Offspring Cohort Study [15
]. Consumption of whole-grain foods was also associated with lower triglyceride concentrations in 827 men and women from the Tehran Lipid and Glucose Study [25
]. Among men and women with diabetes from the Health Professional Follow-up Study and Nurses’ Health Study cereal fiber intake was associated with higher plasma adiponectin levels [19
]. In the present study, no association was observed between consumption of whole-grain bread and HbA1c or plasma values of HDL, triglycerides or adiponectin.
In the present study, the positive association between red meat intake and plasma hs-CRP levels did not remain significant after adjustment for BMI and waist circumference. Since the adipose tissue, particularly from visceral fat depots, is capable of producing pro-inflammatory cytokines that induce hepatic production of CRP and other acute phase proteins, it is plausible that the association observed is mediated by obesity. Inflammation as well as oxidative stress has been suggested to be involved in the pathogenesis of diabetes, cardiovascular diseases and other obesity-related diseases [38
]. However, in a recent cross-sectional analysis among 482 Iranian women, the association between red meat consumption and CRP persisted adjustment for BMI [26
]. The liver enzymes GGT and ALT have been proposed as markers of accumulation of hepatic fat, which is related to increased gluconeogenesis and decreased glycogen storage in the liver [40
]. In the present study, a significant association observed between red meat consumption and GGT persisted after adjustment for measures of obesity, and no association was observed between ALT and red meat consumption. Since GGT is also a potential nonspecific marker of oxidative stress [41
], it is plausible that increased oxidative stress plays an important role in the association between red meat consumption and development of chronic diseases. Also in line with these results, meat consumption was linearly associated with increased serum GGT levels measured after 10 years in CARDIA study [13
] after adjustment for BMI and other lifestyle and dietary factors. Besides obesity, the high consumption of red meat may increase inflammation and oxidative stress because of the high intake of saturated fat, protein, heme-iron, nitrates and nitrite, heterocyclic amines and polycyclic aromatic hydrocarbons, or glycation end products that are usually contained in prepared red meat [45
]. Nevertheless, in an intervention study, a daily intake of ~200 g red meat for 8 weeks among 60 healthy subjects did not elevate plasma levels of GGT or CRP compared to a control group [52
Several prospective studies have suggested that high red meat consumption is associated with a modestly increased risk of colorectal, colon and rectal cancers, cardiovascular disease and type 2 diabetes [1
], whereas high whole-grain intake has been related to reduced risks of colorectal, colon and rectal cancers, cardiovascular diseases and diabetes [5
]. The association of type 2 diabetes risk with higher consumption of red meat and lower consumption of whole-grain bread has been observed in the study population of the present study [53
]. Since circulating levels of GGT and hs-CRP have been related in development of diabetes and cardiovascular disease in several prospective studies [54
], it seems possible that part of the association between red meat and disease risk may be modified by whole-grain intake. The finding in the present study suggests that the positive association between red meat consumption and circulating levels of hs-CRP depends on consumption of whole-grain bread. However, this finding needs to be verified.
The present study was conducted in a cross-sectional design, which complicates the drawing of causal inferences. In the present study, we had data available from a single blood drawing only, which might have introduced random measurement error in determining biomarkers. However, most of the markers presented here have been shown to have a suitable reliability for epidemiological studies [58
]. The dietary data were collected using a food frequency questionnaire (FFQ), which is a common tool in nutritional epidemiology to rank the participants according to their food consumption. FFQs tend to overestimate the amount of consumed foods when compared to dietary recalls and food diaries, therefore the absolute amount of food intake must be interpreted cautiously [60
]. However, fair to good reliability and agreement with 24 h recall data of assessment of red meat and bread consumption have been observed in this study population [32
]. In addition, we based our analysis of whole-grain bread and red meat and their interaction with biomarker levels on quintile distribution, therefore, nondifferential misclassification of food intake should not have affected the results.
In summary, the results of this study suggest that high red meat consumption is associated with modestly higher concentrations of plasma GGT and hs-CRP, whereas high whole-grain bread consumption is related to modestly lower concentrations of GGT, ALT and hs-CRP. The association observed between red meat and hs-CRP is dependent on obesity. This study also suggests that the cross-sectional association of red meat consumption with increased levels of hs-CRP could be modified by high whole-grain bread consumption. Although the strengths of these associations were modest, our observations highlight the hypothesis that dietary factors may modulate these biomarkers, which may be potential mediators related to risk of diabetes and CVD.